Hepatoprotective Mechanisms of TTC39B Deficiency PI: Hsieh, Joanne Project Summary/Abstract This K01 application is designed to provide the necessary resources and training to transition Dr. Joanne Hsieh to full independence in the field of lipid metabolism in liver disease. The proposed work and training will be performed at Columbia University Medical Center (CUMC) in the Department of Medicine, which has demonstrated a commitment to junior faculty mentorship. She will be mentored by Dr. Alan Tall, who is a pre-eminent investigator in lipoprotein metabolism and atherosclerosis. With Dr. Joel Lavine in the Department of Pediatrics as her co-mentor, Dr. Hsieh will transition her focus towards non-alcoholic fatty liver disease (NAFLD). Dr. Lavine has an extensive record of clinical research in adult and pediatric NAFLD, and will be integral in Dr. Hsieh's training in building translational aims into her biomechanistically-focused research. Dr. Hsieh will continue her research on TTC39B, a novel gene significantly associated with HDL-cholesterol in human GWAS. Dr. Hsieh recently showed that deficiency in TTC39B conferred a dramatic protection from steatohepatitis in mice. This hepatoprotection was associated with inhibited sterol-regulatory element binding protein-1 (SREBP-1) activation and decreased lipogenic gene expression. The overall goal of the proposal to determine how decreased expression of specific lipogenic genes contributes the hepatoprotective effects of TTC39B deficiency. Dr. Hsieh will conduct the investigations in a diet-induced mouse model of steatohepatitis that exhibits many of the histological features observed in human NASH, including inflammatory cell infiltration and fibrosis. In the first aim, TTC39B's effect on SREBP-1 activation will be further explored mechanistically to understand the early pathogenesis of NAFLD. The first subaim will determine whether the SREBP-1 inactivation in TTC39B deficiency is driving the protection from steatohepatitis, while the second will investigate the role of phospholipid metabolism in this inactivation. The second aim will explore whether the suppression of phosphatidic acid signalling in TTC39B deficiency prevents the progression of NAFLD to the more severe non-alcoholic steatohepatitis (NASH). Dr. Hsieh's scientific research and career development will be further supported by members of her advisory board, including Dr. Muredach Reilly, Dr. Robert Schwabe, and Dr. Richard Deckelbaum. The mentoring and advisory team will help broaden Dr. Hsieh's approach to scientific hypothesis-testing and ensure her success as an independent investigator.